An Important Function of Petrosiol E in Inducing the Differentiation of Neuronal Progenitors and in Protecting Them against Oxidative Stress

Abstract

Insufficient endogenous neurotrophin supply contributes to neurodegeneration. Meanwhile, neuronal injuries are also attributed to oxidative stress upon toxin exposure. Thus, reconstruction neurite extension and antioxidative stress are the potential strategies for ameliorating neuronal injuries. However, there is no well‐defined therapeutic developed in this regard. In search of such therapeutics, Petrosiol E is identified here as a potent inducer to guide the differentiation of neuronal progenitor cells. Petrosiol E also considerably promotes embryonic stem cell differentiation into neural ectoderm features. Moreover, Petrosiol E reveals an antioxidant function to protect cells from oxidative stress induced by arsenic. Moreover, the molecular mechanism underlying Petrosiol E‐induced neuronal differentiation is uncovered: (a) enhancement of NF‐E2‐related factor 2 (Nrf 2) activity in driving neuronal differentiation; (b) diminishment of oxidative stress. Petrosiol E activates the mitogen‐activated protein kinase and serine/threonine kinase signaling to enhance the activity of Nrf 2. As a result of enhanced Nrf 2 activity, neuronal differentiation is accelerated, and the cellular antioxidation responses are also enforced, even under arsenic‐induced neurotoxicity. Together, the combined results unveil a desirable role of Petrosiol E in driving neuronal differentiation and in combating oxidative stress. This study would open an avenue to develop new therapeutics based on Petrosiol compounds to treat neurodegenerative diseases.

Synthesis and biological activities of petrosiols B and D

“…24 Finally, one-pot global deprotection of 17a,b were achieved with 3 N HCl in reuxing ethanol, delivering petrosiol B (2) in 97% yield and petrosiol D (4) in 98% yield, respectively. The spectroscopic data ( 1 H, 13 C NMR, and HRMS) and specic rotation data of both synthetic petrosiol B and petrosiol D were in good agreement with those of the natural products (see the ESI †).…”

“…With the synthetic petrosiol E in hand, we studied its molecular mechanism in stimulating neuronal differentiation and antioxidative stress in PC12 neuronal progenitor cells. 13 We found that petrosiol E could stimulate the mitogen-activated protein kinase and serine/tyrosine kinase signaling to enhance the activity of Nrf2. We also identied a dual role of petrosiol E in potentiating the differentiation of neuronal progenitors and in protecting them against arsenic-induced oxidative stress in PC12 cells.…”

“…Based on the results from our previous biological study, 13 petrosiols could induce nerve growth factor (NGF)-like neuronal differentiation of PC12 cells in a dose-dependent manner. It thus could provide a potential agent for the prevention and treatment of neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer disease (AD).…”

“…Optical rotations were measured using a polarimeter with a thermally jacketed 2.5 cm cell at approximately 25 C. High-resolution mass spectrometry data (HRMS) were acquired using a Q-TOF analyzer in methanol as solvent. 1 H NMR, 13 C NMR were measured on 400 MHz or 100 MHz spectrometers. Chemicals shis (d) were expressed in ppm relative to residual CHCl 3 , CD 3 OD or TMS.…”

“…Biological activity of the synthetic petrosiols B and D were investigated following our previous evidences on homologue E induced PC12 cells differentiation. 13 To nd out the feasible concentrations in differentiation experiment, petrosiols Fig. 2, petrosiol displayed no obvious effects on cell viability from day 1 to day 5 when the cell was treated with petrosiol (B/D) below the concentration of 5 mg mL À1 .…”